Prostacyclin is a topical hormone produced mainly in the inner wall of the arterial blood vessel of a living body, and is an important factor which adjusts the cellular functions of a living body with its strong physiological activities such as platelet aggregation inhibition activity and vasodilation activity. Attempts have been made to provide this directly as a drug (Clinical Pharmacology of Prostacyclin, Raven Press, N.Y. 1981).
However, natural prostacyclin has an extremely easily hydrolyzable enol ether bond in its molecule so that it is easily hydrolyzed under neutral or acidic conditions to be deactivated. Natural prostacyclin, therefore, cannot be said to be a desirable compound as a drug due to its chemical instability. Under the circumstances, studies have been and are being diligently made of chemically stable synthetic prostacyclin derivatives having physiological activities similar to those of natural prostacyclin.
JP-A-57-54180 and EP 0 045842B1 corresponding thereto disclose prostacylins of the following formula, ##STR1## wherein R.sup.1 is a H, a pharmaceutically acceptable cation or an alcohol residue, R.sup.2 is H or CH.sub.3, A is --CH.sub.2 CH.sub.2 --, (trans)--CH.dbd.CH-- or --C.tbd.C-- and B is an alkyl group represented by ##STR2## (each of R.sup.3 and R.sup.4 is H, CH.sub.3 or C.sub.2 H.sub.5) or a cyclohexyl group,
and it is disclosed that these prostacyclins have activities similar to those of prostacyclin on the aggregation of platelet and blood pressure but that these prostacyclins have higher stability than prostacyclin.
JP-A-3-7275 and EP 0 389162A1 corresponding thereto disclose prostacyclins of the following formula, ##STR3## wherein R.sub.1 is H, a pharmaceutically acceptable cation or an ester residue and R.sub.2 is a C.sub.1-12 linear alkyl group or the like,
that is, 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI.sub.2 derivatives, and it is disclosed that these prostacyclins have excellent stability in a living body.
JP-A-2-57548 discloses prostacyclins of the following formula, ##STR4## wherein R.sub.1 is --COOR.sub.2 . . . , R.sub.2 is H or a pharmaceutically acceptable cation, A is --(CH.sub.2).sub.n -- (n=an integer of 1 to 3), --CH=CHCH.sub.2 --, --CH.sub.2 CH.dbd.CH-- or --CH.sub.2 OCH.sub.2 -- and B is, for example, ##STR5## (R.sub.8 is H, C.sub.1-12 acyl or the like, R.sub.9 is H or C.sub.1-4 alkyl and R.sub.13 is C.sub.5-10 branched alkyl or the like),
and it is disclosed that these prostacyclins have the activities such as the inhibition of platelet aggregation and the reduction of blood pressure,
Further, it is known that prostacyclin derivatives having the oxygen atoms in the 6,9-.alpha.positions of prostacyclin replaced with methine group, i.e., 9(O)-methanoprostacyclin (carbacyclin) is a prostacyclin derivative which satisfies chemical stability (see Prostacyclin, I. R. Vane and S. Bergstrom. Eds. Raven Press, N.Y., pages 31 to 34), and this derivative is expected to be applied as a drug.
U.S. Pat. No. 4,306,076 discloses carbacyclins of the following formula, ##STR6## wherein g is 0, 1, 2 or 3, n is 1 or 2, L.sub.1 is .alpha.-R.sub.3,.beta.-R.sub.4 ; .alpha.-R.sub.4,.beta.-R.sub.3 or a mixture of these (each of R.sub.3 and R.sub.4 is H, CH.sub.3 or F), M.sub.1 is .alpha.-OH,.beta.-R.sub.5 or .alpha.-R.sub.5,.beta.-OH (R.sub.5 is H or CH.sub.3), R.sub.7 is --C.sub.m H.sub.2m --CH.sub.3 (m is an integer of 1 to 5) or the like, Y.sub.1 is trans--CH.dbd.CH--, cis--CH.dbd.CH--, --CH.sub.2 CH.sub.2 -- or --C.tbd.C--, X.sub.1 is --COOR.sub.1 (R.sub.1 is H, C.sub.1-12 alkyl or the like), R.sub.8 is OH, CH.sub.2 OH or H and R.sub.17 is H or a C.sub.1-4 alkyl group,
and it is disclosed that these carbacyclins are useful as an antithrombotic agent, an antiulcer agent and an antasthmatic.
JP-A-58-92637 discloses carbacyclins of the following formula, ##STR7## wherein R.sub.1 is H, a C.sub.1-4 alkyl group or a pharmaceutically harmless cation, and R.sub.2 is a cyclohexyl group, a 4-methylcyclohexyl group or a 1-adamantyl group,
and it is disclosed that these carbacyclins are useful for inhibiting the aggregation of platelet.
JP-A-58-126835 and EP 0 080718A1 corresponding thereto disclose prostacyclins and carbacyclins of the following formula, ##STR8## wherein R.sup.1 is H, C.sub.1-4 alkyl, a pharmaceutically acceptable ammonium cation or a metal cation, each of R.sup.2 and R.sup.3 is independently H or a protective group such as alkanoyl, R.sup.4 is H or C.sub.1-4 alkyl, X is --O-- or --CH.sub.2 --, Y is --C.tbd.C-- or trans--CH.dbd.CW-- (W is U, Br or F) and Z is C.sub.6-9 alkyl optionally substituted with one or two Fs or C.sub.1-4 alkyls, or optionally substituted arylmethyl or aryloxymethyl,
and it is disclosed that these compounds enhance the platelet aggregation activity and reduce the anti-hypertension activity.
International Patent Publication WO 83/04021 discloses carbacyclins of the following formula, ##STR9## wherein A is carboxy, cyano, tetrazolyl, --COOR.sub.3 (R.sup.3 is C.sub.1-4 alkyl or a pharmaceutically acceptable cation) or --CONR.sup.1 R.sup.2 (each of R.sup.1 and R.sup.2 is H, phenyl, C.sub.1-5 alkyl or C.sub.1-4 alkylsulfonyl, or R.sup.1 and R.sup.2 may form together a C.sub.3-6 .alpha., .omega.-alkylene group), B is --O-- or --CH.sub.2 --, Y is vinylene optionally substituted Br or --C.tbd.C--, R.sup.4 is H or tetrahydropyran-2-yl, R.sup.5 is C.sub.5-9 alkyl optionally interrupted by 1 or more oxygen atoms, --CH.dbd.CH--, --C.tbd.C--, phenoxymethyl optionally substituted with halogen or trifluoromethyl or C.sub.3-5 alkenyloxymethyl, R.sup.6 is H or C.sub.1-4 alkyl, R.sup.7 is H, halogen, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, and R.sup.8 is H, halogen, cyano, nitro, hydroxy or C.sub.2-5 alkanoylamide, provided that, when R.sup.5 is C.sub.5-9 alkyl not substituted or not interrupted by any oxygen atom, --CH.dbd.CH--, --C.tbd.C-- or phenoxymethyl optionally substituted with halogen or trifluoromethyl, either R.sup.7 or R.sup.8 is other than H, or A is other than carboxy and --COOR.sup.3,
and it is disclosed that these carbacyclins show cellular protection, aggregation inhibition and low hypotension activities and are of an activity-sustaining type.
German Patent Laid-Open Publication DE 3408699A1 discloses carbacyclins of the following formula, ##STR10## wherein R.sub.1 is OR.sub.2 or R.sub.3 (R.sub.2 is H, C.sub.1-10 alkyl, C.sub.5-6 cycloalkyl or the like, and R.sub.3 is C.sub.1-10 alkyl or the like), A is --CH.sub.2 CH.sub.2 --, trans--CH.dbd.CH-- or --C.tbd.C--, W is ##STR11## or a functional derivative of any one of these, D is ##STR12## a C.sub.1-3 linear saturated alkylene group or a C.sub.2-5 branched saturated, or linear or branched unsaturated alkylene group, n is 1, 2 or 3, E is --C.tbd.C-- or --CR.sub.6 --CR.sub.7 -- (each of R.sub.6 and R.sub.7 is independently H, C.sub.1-5 alkyl or halogen), or when R.sub.1 is R.sub.3, E is --CH.sub.2 CH.sub.2 --, R.sub.4 is C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, and R.sup.5 is a hydroxyl group optionally protected.
Finally, JP-A-2-295950 and EP 0396024A2 corresponding thereto disclose prostacyclin and carbacyclin of the following formula, ##STR13## wherein X is --O-- or --CH.sub.2 --,
and it is also disclosed that these compounds show the oral-absorption property suitable for oral administration.
Meanwhile, a compound which shows the activity for the inhibition of the hypertrophy of a blood vessel is useful, for example, as a drug for inhibiting the hypertrophy and occlusion of a blood vessel caused mainly by the proliferation of blood vessel smooth muscle cells after various angioplastic operations, arterial bypass operations and internal organic transplantation, as a drug for the prevention and therapy of blood vessel hypertrophy and occlusion (or a drug for the inhibition of the proliferation of blood vessel smooth muscle cells) and further as a drug for the prevention and therapy of arterial sclerosis.
However, it has not been reported that prostacyclin or its derivatives have the activity for inhibiting the blood vessel hypertrophy.